There are many diseases well known to affect human airways. Such diseases include, for example, cancer, cystic fibrosis, emphysema, asthma, tuberculosis and pneumonia. The study of these diseases and their treatment has, however, been hindered by the lack of a predictive animal model for a human airway, and particularly a diseased human airway and more particularly a human CF airway.
Cystic fibrosis (CF) is a lethal, inherited disease caused by abnormalities in epithelial cell function. The most morbid and life limiting aspect of cystic fibrosis involves pulmonary manifestations. The primary manifestation appears to be abnormal mucocilliary clearance. CF patients develop thick mucous that is difficult to clear and ultimately leads to obstruction of the airways. In addition, the lungs of CF patients become colonized with staphylococcus and pseudomonas and the patients suffer from recurring life-threatening pulmonary infections.
The gene responsible for CF is approximately 250 kbp and encodes a protein of 1480 amino acids. In approximately 70% of the individuals with CF, the CF gene is apparently dysfunctional due to a 3-bp deletion, which results in the deletion of a single amino acid (Phe-508). However, more than 170 different mutations have been identified in the remaining 30% of patients.
The CF gene product--the cystic fibrosis transmembrane conductance regulator (CFTR)--is thought to be a chloride channel normally expressed on the apical surface of epithelial cells. When the CF gene is dysfunctional, as in cystic fibrosis, the epithelial cells are incapable of properly transporting chloride and develop coordinate defects in sodium and water transport.
The primary pathogenic processes in CF involve the components of the lung that contribute to the mucous: the goblet cells which line the surface epithelium and the submucosal glands found in the proximal airway whose function is to produce mucous and transport it into the airway lumen. Expression of CFTR has recently been localized to both cell types. However, most animal models, including rodents and rabbits, lack submucosal glands in their airways, making them unsuitable for the study of cystic fibrosis and other lung diseases of humans.
The deficiencies of the currently available animal models for human cystic fibrosis lungs are best demonstrated by a study recently reported in Science [J. N. Snouwaerl et al., "An Animal Model for Cystic Fibrosis made By Gene Targeting", Science, 257, pp. 1083-88 (1992)] in which investigators developed a mutant strain of mice deficient in the CF gene. While these animals developed many manifestations of cystic fibrosis, they lacked the lung pathology which characterizes the human CF disease.
Accordingly, in order to study the causes and pulmonary manifestations of cystic fibrosis and other human lung diseases, to study the effect of various agents, environmental and otherwise, on human airways and, particularly, to study the efficacy of various potential therapies or agents for human lung disorders, especially CF, a useful animal model of a human airway is urgently needed.